Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Drug Analysis
2.3. Population Pharmacokinetic Modelling
2.4. Monte Carlo Simulation and Probability of Target Attainment
3. Results
3.1. Study Population
3.2. Population Pharmacokinetic Modelling
3.3. Monte Carlo Simulation for Estimating PK/PD Target Attainment
4. Discussion
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Characteristic | Value | |
---|---|---|
Age (years) | 71.0 (61.8–79.0) | |
Gender (male/female) | 86/46 | |
Body weight (kg) | 73.5 (65.0–89.0) | |
BMI (kg/m2) | 25.7 (22.5–30.1) | |
Serum creatinine (mg/dL) | 0.90 (0.68–1.36) | |
eGFR (mL/min/1.73 m2) | 83.7 (50.5–101.7) | |
Serum albumin (g/L) | 3.1 (2.7–3.4) | |
Type of infection, n (%) | ||
Hospital-acquired pneumonia | 38 (28.8) | |
Endocarditis | 27 (20.5) | |
Bloodstream infection | 22 (16.6) | |
Community-acquired pneumonia | 20 (15.2) | |
Bone and joint infections | 9 (6.8) | |
Skin and soft tissue infections | 9 (6.8) | |
Device-related infections | 4 (3.0) | |
CNS infections | 3 (2.3) | |
Patients with identified microbiological isolates, n (%) | 80 (60.6) | |
Ceftobiprole treatment | ||
Median dose (mg daily) | 1500 (1000–1500) | |
Trough concentration (mg/L) | 7.6 (4.9–11.7) | |
Length of treatment (days) | 10.0 (2.0–81.0) | |
Patients with co-administered antibiotics, n (%) | 88 (66.7) | |
Treatment outcome in assessable patients (n = 126) | ||
N. of patients with microbiological eradication | 118 (96.7) | |
N. of patients with clinical cure | 88 (69.8) |
Parameter | Base Model Estimate (% RSE) | Covariate Model Estimate (% RSE) | Bootstrap Median (95% CI) | |
---|---|---|---|---|
Typical values | ||||
CL (L/h) | 3.43 (7.33) | 1.7 (11.9) | 1.63 (1.48–1.76) | |
V1 (L) | 21.29 (13.5) | 14.77 (19.7) | 14.12 (14.37–16.72) | |
Q2 (L/h) | 7.12 (19.0) | 6.11 (13.6) | 6.54 (5.89–7.61) | |
V2 (L) | 35.79 (44.2) | 46.16 (34.8) | 46.56 (38.75–50.76) | |
Q3 (L/h) | 4.04 (31.5) | 42.41 (61.6) | 44.71 (31.57–67.84) | |
V3 (L) | 4.08 (26.9) | 4.76 (13.9) | 4.74 (4.30–6.00) | |
Covariate effect | ||||
eGFR on CL | - | 0.011 (12.6) | 0.01 (0.010–0.012) | |
Gender on V1 | - | 0.39 (54.8) | 0.38 (0.29–0.49) | |
Inter-individual variability | ||||
on CL (%CV) | 61.9 (8.6) | 47.4 (8.43) | 47.38 (43.92–50.90) | |
on V1 (%CV) | 68.5 (29.6) | 75.3 (19.4) | 79.52 (50.91–93.09) | |
on Q2 (%CV) | 29.6 (46.5) | 35.0 (34.5) | 21.23 (16.10–37.19) | |
on V2 (%CV) | 717.4 (21.2) | 268.1 (19.4) | 477.17 (224.12–762.68) | |
on Q3 (%CV) | 80.9 (37.6) | 235.2 (45.1) | 123.01 (58.18–360.44) | |
on V3 (%CV) | 50.9 (40.2) | 30.7 (30.0) | 26.44 (18.14–31.76) | |
Correlation | ||||
CL and V1 | - | 0.6 (24.8) | 0.52 (0.40–0.65) | |
Residual variability | ||||
a | 1.43 (12.0) | 1.44 (13.4) | 1.49 (1.07–1.65) | |
b | 0.22 (6.8) | 0.22 (5.8) | 0.23 (0.21–0.25) |
Ceftobiprole Dosages and Classes of eGFR | MRSA | MRSE | ||
---|---|---|---|---|
Quasi-Optimal PK/PD Target | Optimal PK/PD Target | Quasi-Optimal PK/PD Target | Optimal PK/PD Target | |
eGFR < 30 mL/min/1.73 m2 | ||||
250 q12h EI | 95.9 | 58.2 | 88.1 | 52.9 |
250 q12h CI | 99.7 | 79.1 | 91.3 | 73.9 |
250 q8h EI * | 98.8 | 80.7 | 90.7 | 75.2 |
250 q8h CI * | 100 | 91.4 | 91.4 | 85.4 |
eGFR 30–50 mL/min/1.73 m2 | ||||
500 q12h EI | 98.6 | 78.4 | 90.4 | 72.9 |
500 q12h CI | 99.9 | 94.5 | 91.4 | 88.1 |
500 q8h EI * | 99.7 | 92.6 | 91.2 | 85.8 |
500 q8h CI * | 100 | 98.4 | 91.4 | 90.7 |
eGFR 51–80 mL/min/1.73 m2 | ||||
500 q8h EI | 99.5 | 83.2 | 91.1 | 77.1 |
500 q8h CI | 100 | 96.8 | 91.4 | 89.7 |
500 q6h EI * | 99.4 | 93.4 | 91.3 | 86.6 |
500 q6h CI * | 100 | 98.9 | 91.4 | 91.0 |
eGFR 81–130 mL/min/1.73 m2 | ||||
500 q8h EI | 97.2 | 66.0 | 89.4 | 60.8 |
500 q8h CI | 100 | 90.5 | 91.4 | 84.8 |
500 q6h EI * | 99.4 | 83.5 | 91.0 | 77.7 |
500 q6h CI * | 100 | 96.5 | 91.4 | 90.0 |
eGFR > 130 mL/min/1.73 m2 | ||||
500 q8h EI | 75.2 | 22.2 | 69.3 | 18.3 |
500 q8h CI | 99.2 | 66.7 | 91.1 | 61.3 |
500 q6h EI * | 89.2 | 41.1 | 82.3 | 36.2 |
500 q6h CI * | 99.8 | 82.3 | 91.2 | 77.1 |
500 q4h EI * | 98.4 | 72.2 | 90.3 | 66.7 |
500 q4h CI * | 100 | 92.5 | 91.4 | 86.4 |
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Cojutti, P.G.; Giuliano, S.; Pascale, R.; Angelini, J.; Tascini, C.; Viale, P.; Pea, F. Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections. Microorganisms 2023, 11, 2964. https://doi.org/10.3390/microorganisms11122964
Cojutti PG, Giuliano S, Pascale R, Angelini J, Tascini C, Viale P, Pea F. Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections. Microorganisms. 2023; 11(12):2964. https://doi.org/10.3390/microorganisms11122964
Chicago/Turabian StyleCojutti, Pier Giorgio, Simone Giuliano, Renato Pascale, Jacopo Angelini, Carlo Tascini, Pierluigi Viale, and Federico Pea. 2023. "Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections" Microorganisms 11, no. 12: 2964. https://doi.org/10.3390/microorganisms11122964
APA StyleCojutti, P. G., Giuliano, S., Pascale, R., Angelini, J., Tascini, C., Viale, P., & Pea, F. (2023). Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections. Microorganisms, 11(12), 2964. https://doi.org/10.3390/microorganisms11122964